Vadlamani K. Prasad

Influence of tablet dissolution on furosemide bioavailability: a bioequivalence study

In order to evaluate the in vitro dissolution and in vivo bioavailability relationship for furosemide, a bioequivalence study was carried out. Furosemide (40 mg) was administered orally to 12 normal volunteers in a 6 × 6 crossover design using six products (five tablets and one solution) obtained from three pharmaceutical companies. Plasma and urine concentrations of furosemide were quantitated by high-performance liquid chromatography (HPLC). Plasma furosemide profiles were analyzed by non-compartmental methods. Compared to the oral solution, all of the formulations exhibited lower peak furosemide concentrations, longer mean residence times, and, in some cases, diminished bioavailability (range, 66–96%). Similar results were obtained when the reference product (a rapidly dissolving tablet) was used as the standard. All of the products failed the 75/75 rule when compared to either reference standard, apparently because of large intersubject variability. The total amount of furosemide excreted in urine could be associated with the percentage drug dissolved (in vitro) at 30 min. The pH 5.6 dissolution medium (compared to pH 4.6) appears to be an appropriate test medium for assuring batch uniformity and bioequivalence of furosemide products.

Dissolution medium—a critical parameter to identify bioavailability problems of furosemide tablets

The pH-solubility profiles of furosemide bulk drug and the dissolution profiles of two brands of furosemide tablets as a function of pH have been determined. The dissolution rate increased as the pH of the medium increased. Even though dissolution rate differences were noted around the pKa (3.60) of furosemide, such differences were negligible in the phosphate buffer region. One of these brands was alleged to cause therapeutic failures. The brand that dissolved poorly at pH 4.6 also exhibited inferior bioavariability. The data suggests the need for careful selection of pH and buffers composing dissolution media to make in vitro results meaningful and consistent with in vivo data.

Improved method for the analysis of furosemide in plasma by high-performance liquid chromatography.

Modifications of existing rapid high-performance liquid chromatographic procedures for the determination of furosemide in plasma were made in order to achieve greater sensitivity. To a small volume of plasma was added in internal standard structurally related to furosemide. Then, following previously described procedures, acetonitrile was added to precipitate the proteins and the clear supernatant was separated. However prior to injection of the supernatant the pH and composition of the sample were adjusted. This modification of the sample enabled an injection volume of up to 300 microliters of the supernatant to be injected onto the chromatographic column. The effluent was monitored spectrofluorimetrically. A standard linear calibration curve with a mean precision of +/- 4.4% was obtained for plasma samples containing 20--900 ng/ml of furosemide. Two structurally related compounds were used as internal standards in the furosemide assay.

Importance of media selection in establishment of in vitro-in vivo relationships for quinidine gluconate

Abstract The dissolution profiles of two different commercial formulations of controlled release 324 mg quinidine gluconate tablets were investigated and their bioavailability differences were associated with in vitro results. One of the marketed brands which was not approved by the Food and Drug Administration was alleged by some patients to have no therapeutic effect when taken orally. Dissolution profiles using the paddle method at 100 rpm in different dissolution media revealed wide differences between these two products. The dissolution rates of the two products were significantly different in water, acetate buffer pH 5.4 and phosphate buffer pH 5.4. However, the dissolution profiles were similar for the two products with respect to rate and extent in simulated gastric fluid (no enzymes) and pH 7.4 phosphate buffer. Bioavailability data for these two products showed significant differences among various in vivo parameters. A reformulated product with comparable bioavailability to the FDA-approved product also had similar dissolution profiles in the systems studied earlier. These findings confirmed the importance of the screening and judicious selection of dissolution medium as well as the predictive usefulness of a dissolution test in the quality control of sustained (or controlled) released quinidine gluconate formulations.

The analysis of 4-chloro-5-sulfamoylanthranilic acid in the bulk material and pharmaceutical preparations of furosemide by a high-performance liquid chromatographic method

Abstract The current USP procedure for the limit tests for 4-chloro-5-sulfamoyanthranilic acid (CSA) in furosemide preparations is a tedious and non-specific method. A simple, sensitive and specific method for the quantitative analysis of CSA from bulk materials and pharmaceutical preparations is described. The procedure consists of extraction into 0.1 N sodium hydroxide solution, dilution, addition of internal standard and injection onto a high-performance liquid Chromatograph. The eluate is monitored by ultraviolet absorption at 280 nm. Utilizing this procedure, CSA was quantitatively analyzed from furosemide tablets, furosemide injection and furosemide bulk powder.

Simultaneous determination of prednisolone acetate, prednisolone, prednisone, cortisone and hydrocortisone in swine plasma using solid-phase and liquid—liquid extraction techniques

A high-performance liquid chromatographic (HPLC) method for the simultaneous determination of prednisolone acetate (PA), prednisolone (PO), prednisone (PN), cortisone and hydrocortisone in swine plasma is described. Extraction of the steroid mixture from swine plasma with dexamethasone as internal standard was accomplished by solid-phase extraction (SPE) or the more traditional liquid-liquid extraction (LLE) techniques. These compounds were analyzed by normal-phase HPLC with ultraviolet detection. Although a detectable sensitivity of 5 ng/ml is achieved by the SPE technique, the practical sensitivity is established as 10 ng/ml. Conversely, the practical sensitivity is 5 ng/ml for all compounds by the LLE technique. Calibration curves were found to be linear between 10 and 500 ng/ml by the SPE technique and between 5 and 100 ng/ml by the LLE technique. The average recovery of the steroids PA, PO and PN at 20 ng/ml is between 70 and 90%. PA is stable for up to 3 h in swine plasma at room temperature (22 degrees C) but is completely converted to PO within 24 h. PA is stable in swine plasma in an ice bath for over 24 h. The usefulness of this analytical technique is demonstrated by the intraperitoneal administration of 125 mg of PA to swine and the quantitative determination of PA, PO and PN in the plasma as a function of time.

The Effect of Food on the Absorption of Controlled-Release Theophylline in Mini-Swine

The effect of differing fat contents of food on the bioavailability of theophylline following a 400-mg single dose of Theo-24 was studied in mini-swine. The pharmacokinetics of theophylline, following the intravenous administration of aminophylline equivalent to 5 mg/kg as a single dose, were also studied in the same animals. The terminal plasma half-life of theophylline following an i.v. dose was found to be approximately 24 hr. The volume of distribution, Vdext, and clearance following the i.v. dose were approximately 0.7 liter/kg and 0.023 liter/hr/kg, respectively. The terminal half-life of theophylline following the administration of theophylline capsules under fasting conditions was 21 hr. The average bioavailability under fasting conditions was approximately 80% compared to the i.v. dose. Food appeared to have decreased the rate of absorption but no significant effect on the extent of absorption.

An HPLC Procedure for the Analysis of Furosemide in Pharmaceuticals-Analysis of Furosemide Tablets and Furosemide Injection

Abstract A simple and specific procedure was developed for the analysis of furosemide from tablets and injections. The procedure consists of extracting furosemide into aqueous sodium hydroxide, addition of the internal standard, appropriate dilution and injection onto a u Bondapak C18 reversed phase column. The mobile phase consisted of a solvent containing acetonitrile and aqueous sodium acetate and the eluate was monitored by either U.V. absorption or spectrofluorimetry. A standard linear calibration curve was obtained for direct standard solutions containing 75 ng to 500 ng on column. This procedure was successfully used to analyze furosemide tablets (individual assay) and injections.

Thiazides XII: A Simple HPLC Method for Determination of Thiazides in Urine

Abstract A simple HPLC procedure is described for the determination of nine thiazides in the urine samples.

Capillary gas chromatographic (GC) analysis of nitroglycerin and its denitration products in plasma.

A convenient, specific, and sensitive capillary gas chromatographic (GC) assay for analyzing nanogram concentrations of nitroglycerin and its dinitro- and mononitrometabolites in plasma has been developed. Using a bonded-phase (DB-1) 30-m, 1-µm-thick film capillary column and a 1-m, 5-µm-thick film precolumn, separation of nitroglycerin and all four partially nitrated metabolites was achieved in less than 15 min. On-column injection, electron capture detection, and isothermal operation at 100°C yielded a linear extraction curve over a 300-ng/ml range without any need to concentrate sample extracts. Using methyl t-butyl ether as extraction solvent and o-chloronitrobenzene as internal standard, recoveries from plasma spiked at levels greater than 10 ng/ml approximated 35% for the 1-monometabolite, 40% for the 2-monometabolite, and greater than 90% for all others. The method was employed in a pharmacokinetic study of nitroglycerin administered intravenously to beagle dogs. Plasma samples were collected at various time points and analyzed.